Improved process for preparing idelalisib

ABSTRACT

The present invention relates to an improved process for preparing Idelalisib (1). In this process, acid addition salts of idelalisamine (2) are useful intermediates for purification purposes.

BACKGROUND OF THE PRESENT INVENTION

This invention relates to the preparation of pharmaceuticals and theirintermediates. In particular it relates to an improved process ofpreparing idelalisib (1). The process runs via acid addition salts ofidelalisamine (2). Idelalisamine (2) is a late stage intermediate in theprocess for preparing idelalisib (1). The acid addition salts ofidelalisamine can be purified easily via precipitation/crystallizationand provide an easy purification option for a late stage intermediate inthe process for preparing idelalisib (1).

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Idelalisib (WO2005113556) is a PI3Kδ inhibitor of structure (1) and isused for the treatment of patients with follicular lymphoma, relapsedsmall lymphocytic lymphoma and relapsed chronic lymphocytic leukaemia.

WO2005113556 describes the preparation of idelalisib as depicted below.

The process for preparing idelalisib as described in WO2005113556requires chromatographic purification steps for intermediates (4) and(3), and for idelalisib (1). Chromatographic purification steps aretedious and expensive process steps on an industrial scale. Therefore,there is a need for alternative methods which reduce the number ofchromatographic purification steps in the preparation of idelalisib.

SUMMARY OF THE INVENTION

The present invention relates to improvement of the overall efficiencyin the process for preparing idelalisib (1) and to the acid additionsalts of idelalisamine (2).

DETAILED DESCRIPTION OF THE INVENTION

Treatment of idelalisamine (2) with several acids, results in isolationof the corresponding idelalisamine acid addition salt in high yield andpurity. Also when crude intermediate (3) was used as starting materialfor preparing idelalisamine, the acid addition salt of idelalisamine wasisolated in a yield and purity comparable with the original procedure ofWO2005113556. This precipitation and/or crystallisation of an acidaddition salt of idelalisamine obviates earlier chromatographic steps inthe synthesis, thereby making the process more efficient and lesscostly. The acid addition salt of idelalisamine can be used as such inthe final step for preparing idelalisib (1).

In a first aspect the invention relates to processes for preparingidelalisib (1) that have acid addition salts of idelalisamine (2) asintermediate.

Several acids were tested for their capability to form acid additionsalts with idelalisamine (2) and for their usefulness in thepurification of idelalisamine. Some of the tested acids were found toproduce acid addition salts of idelalisamine that are easy toprecipitate or crystallise, while others formed only oils, very finesuspensions, or material that liquefied during filtration.

Best results were achieved using hydrochloric acid, benzoic acid, oxalicacid, malonic acid, fumaric acid, tartaric acid, ethanesulphonic acid,or p-toluenesulphonic acid and the acid addition salts of these acidsare the preferred salts of the current invention. Of these, the acidaddition salt of hydrochloric acid is the most preferred. Thehydrochloric acid salt produces a crystalline material from severalsolvents such as 1,4-dioxane, EtOAc, THF, 2-Me-THF, CHCl₃, CH₂Cl₂,Toluene and t-BuOH, which are the preferred solvents in this invention.Most preferred solvent is 2-Me-THF.

The results of the tests are summarized in the table below.

Acid 1,4-Dioxane EtOAc THF 2-Me-THF CHCl₃ HCl  85% 92% 92%  100% 30.4%H₂SO₄ No 76.9% (oil) HNO₃ No H₃PO₄ * 17.3%   17% (oil) (oil) Formic acidTraces Acetic acid no No No No Benzoic acid No 31.6% Oxalic acid 2.9%48% 86.5% 81.1% Malonic acid 79.3% Fumaric acid 79% Maleic acid No (oil)Tartaric acid 36.5% EtSO₃H 106 ** 97% Traces (oil) p-TosOH No No 93.6% *0.66 equivalents used ** sticky white crystals (oil)suspension/colloid/liquefied during isolation

Should the precipitation of the acid addition salt of idelalisamine (2)not lead to material of sufficient quality, the acid addition salt canbe recrystallized by methods generally known in the art. Typicalexamples of such methods include: allowing a warm solution of the saltto cool down; allow the solvent of a solution of the salt to slowlyevaporate, and; addition of an anti-solvent to a solution of the salt.

In a second aspect the invention relates to acid addition salts ofidelalisamine (2). Preferred acid addition salts of idelalisamine (2)are the salts of hydrochloric acid, benzoic acid, oxalic acid, malonicacid, fumaric acid, tartaric acid, ethanesulphonic acid, orp-toluenesulphonic acid. Most preferred salt is the hydrochloride salt.

The salts of this invention can be used as late starting material forpreparing idelalisib (1). Adjustments to the process as described inWO2005113556 to compensate for the use of the salts as starting materialinstead of the free base are routine to the person skilled in the art.

The new salts allow substituting one or more of the chromatographicpurification steps in the process of WO2005113556 with purification byprecipitation and/or crystallisation in the idelalisamine stage.Therewith making the process of preparing idelalisib (1) more efficienton industrial scale from a time and cost perspective.

The invention will be further illustrated by the following,non-limiting, examples.

EXAMPLES Example 1. Preparation of HCl Salts of Idelalisamine (2) inVarious Solvents

0.12 gram (0.357 mmol) of idelalisamine with 88% purity was dissolved in3 ml of solvent. 0.032 ml of hydrochloric acid (37%, 0.357 mmol) wasadded. The mixture was heated to 90° C. (70° C. for ethylacetate, 35° C.for CH2Cl2) and allowed to cool down to 0° C. (20° C. for 1,4-dioxane).

Solvent Yield Purity Ethylacetate 0.110 g (90%) 97.6% Butane-2-ol 0.074g (62.1%) Toluene 0.062 g (52.0%) 1,4-dioxane 0.101 g (83%) 98.5% THF0.110 g (91%) 98.8% 2-Me-THF 0.122 g (102%) CH₂Cl₂ 0.097 (79%) 97.2%

Example 2. Preparation of Salts of Idelalisamine (2) with Various Acidsin THF

0.12 gram (0.357 mmol) of idelalisamine with 88% purity was dissolved in3 ml of THF. 0.357 mmol of acid was added. The mixture was heated to 60°C. and allowed to cool down to 0° C.

Acid Yield Ethanesulphonic acid 0.141 g (97%) Fumaric acid 0.117 g (79%)Sulphuric acid — Acetic acid — Benzoic acid Precipitates at 0° C.,dissolves at 15° C. Nitric acid — P-toluenesulphonic acid — Phosphoricacid 0.016 g (11.4%), liquefies during filtration Oxalic acid 0.066 g(48%) Maleic acid — Hydrochloric acid 0.106 g (89%)

Example 3. Preparation of Salts of Idelalisamine (2) with Various Acidsin 2 Me THF

0.12 gram (0.357 mmol) of idelalisamine with 88% purity was dissolved in3 ml of 2-Me-THF. 0.357 mmol of acid was added. The mixture was heatedto 60° C. and allowed to cool down to 0° C.

Acid Yield Sulphuric acid 0.108 g (77%), liquefies during filtrationAcetic acid — Benzoic acid 0.047 g (31.5%) P-toluenesulphonic acid 0.156g (94%) Phosphoric acid 0.016 g (11.4%), liquefies during filtrationOxalic acid 0.119 g (86%) Maleic acid oil Malonic acid 0.113 g (79%)(2R,3R)-tartaric acid 0.058 g (36.5%)

Example 4. Preparation of Salts of Idelalisamine (2) with Various Acidsin 1,4-Dioxane

0.12 gram (0.357 mmol) of idelalisamine with 88% purity was dissolved in3 ml of 1,4-dioxane. 0.357 mmol of acid was added. The mixture washeated to 90° C. and allowed to cool down to 20° C.

Acid Yield Oxalic acid 0.004 g (3.49%) Acetic acid —

Example 5. Preparation of Salts of Idelalisamine (2) with Various Acidsin Chloroform

0.12 gram (0.357 mmol) of idelalisamine with 88% purity was dissolved in3 ml of 2 Me THF. 0.357 mmol of acid was added. The mixture was heatedto 55° C. and allowed to cool down to 0° C.

Acid Yield Hydrochloric acid 0.030 g (30.4%) Acetic cid —Ethanesulphonic acid Liquefies during filtration Oxalic acid 0.093 g(66.9%)

Example 6. Purification of Idelalisamine (2) Via Hydrochloric AcidExtraction

0.442 g (1.383 mmol) of idelalisamine with 93% purity was dissolved in10 ml of dichloromethane and extracted with 19 ml of 2% HCl. Afterseparating the layers, the organic phase was extracted with 6 ml of 1.5%HCl.

A solution of 50% NaOH was added to the combined aqueous phases until apH of approximately 10 was reached. A white precipitate is formed whichis filtered and washed with 5 ml of water. The product was dried in avacuum oven at 40° C. under a pressure of 100 torr with nitrogenstripping for 5 hours.

Yield: 0.321 g (77%) of white crystals with a purity of 98%.

Example 7. Preparation of tert-butyl(S)-(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate(3)

6.41 g, (14.39 mmol) of compound (4) was dissolved in 55 ml acetic acidat room temperature. Zinc dust (5.65 g, 86 mmol) was added in smallportions. After each addition, a rise in internal temperature wasobserved. The reaction mixture was allowed to cool below 35° C. beforethe next portion was added. Addition took ca. 30 min.

After 3 hours the reaction mixture was filtered through celite, thefilter cake was washed with a small amount of acetic acid and thefiltrate was concentrated in vacuo.

The resulting oil was split in ca 7:3 ratio, the smaller portion waskept for future experiments and the larger portion was diluted withapproximately 20 ml of CH₂Cl₂. The CH₂Cl₂ solution was filtered throughcelite to remove solid material present in the solution and purified bychromatography using MPLC.

2.22 g (5.59 mmol, 55.5%) of compound (3) was isolated.

Example 8. Preparation of Idelalisamine (2) Starting from Purified (3)

2.22 g (5.59 mmol) of compound (3) isolated after column chromatographyas described in example 7 was dissolved in 6 ml of CH₂Cl₂. 3.82 g (33.5mmol) of trifluoroacetic acid (TFA) was added and the reaction mixturewas stirred at room temperature for 5 hours. The reaction mixture wasconcentrated in vacuo and partitioned between 10 ml of CH₂Cl₂ and 60 mlof 10% K₂CO₃. The aqueous layer was extracted with additional CH₂Cl₂ andthe combined organic layers were washed with water and brine, dried overMgSO₄, filtered, concentrated and dried in vacuo for 2 hours to resultin 1.49 g (5.01 mmol, 89.7%) of idelalisamine (2) with a purity of 93%.

Yield starting from compound (4) following examples 7 and 8: 49.7%

Example 9. Preparation of Idelalisamine.HCl (2).HCl Starting from Crude(3)

The 0.3 fraction of crude (3) (2.5 g) that was set aside in example 7was dissolved in 10 ml of CH₂Cl₂, filtered over celite and evaporated todryness to yield 2 gram of an oil.

1 gram of this oil was dissolved in 3 ml of CH₂Cl₂. 0.8 g (7.1 mmol) oftrifluoroacetic acid (TFA) was added and the reaction mixture wasstirred at room temperature for 3 hours.

The reaction mixture was concentrated in vacuo and partitioned between 5ml of CH₂Cl₂ and 20 ml of saturated NaHCO₃. The aqueous layer wasextracted with additional CH₂Cl₂ and the combined organic layers werewashed with water and brine, dried over MgSO₄, filtered, concentratedand dried in vacuo for 30 min to result in 0.576 g (1.124 mmol, 95%) ofcrude idelalisamine (2).

This crude material was dissolved in 5 ml of 2-Me-THF and 0.175 ml (2mmol) of 35% HCl was added. The mixture was stirred at 0° C. for 15 min.and filtered. The residue was washed with 2-Me-THF and dried in vacuo at40° C. overnight to result in 0.369 g of idelalisamine.HCl (2).HCl witha purity of 98.4% and a total assay of 79.7%.

Yield starting from compound (4) following examples 7 and 9: 51.4%.

1. In a process for synthesizing preparing idelalisib of formula (1)from idelalisamine of formula (2),

the improvement for which comprises isolating an acid addition salt ofidelalisamine before its chemical conversion to idelalisib.
 2. Theprocess of claim 1, wherein the acid in the acid addition salt ofidelalisamine (2) is hydrochloric acid, benzoic acid, fumaric acid,malonic acid, tartaric acid, ethanesulphonic acid, p-toluenesulphonicacid or oxalic acid.
 3. The process of claim 1, wherein the acid in theaddition salt of idelalisamine is hydrochloric acid.
 4. A process whichcomprises: (a) mixing idelalisamine free base of formula 2

with an acid selected from hydrochloric acid, benzoic acid, fumaricacid, malonic acid, tartaric acid, ethanesulphonic acid,p-toluenesulphonic acid or oxalic acid, in a solvent or solvent mixtureand (b) isolating the idelalisamine acid addition salt.
 5. A process ofclaim 4, wherein the mixing of idelalisamine free base with anappropriate acid of step (a) is performed in a crude reaction mixture.6. A process according to claim 5, wherein step (a) is performed in asolvent or solvent mixture comprising at least one of: 1,4-dioxane,EtOAc, THF, 2-Me-THF, CHCl₃, CH₂Cl₂, Toluene and t-BuOH.
 7. A processaccording to claim 4, wherein step (a) is performed in 2-Me-THF or asolvent mixture comprising 2-Me-THF.
 8. A process according to claim 4,wherein step (b) is performed by crystallising the idelalisamine acidaddition salt.
 9. A process according to claim 4, which furthercomprises purifying said isolated idelalisamine acid addition salt whichcomprises the steps of: (i) dissolving the salt in a solvent, and (ii)inducing crystallisation of the idelalisamine acid addition salt. 10.The process of claim 9 wherein the solvent in step (i) is chosen from1,4-dioxane, EtOAc, THF, 2-Me-THF, CHCl₃, CH₂Cl₂, Toluene and t-BuOH.11. The process of claim 9 wherein the solvent in step (i) is 2-Me-THF.12. An acid addition salt of idelalisamine of formula (2)


13. The acid addition salt of claim 12, wherein the acid in the acidaddition salt is hydrochloric acid, benzoic acid, fumaric acid, malonicacid, tartaric acid, ethanesulphonic acid, p-toluenesulphonic acid oroxalic acid.
 14. An acid addition salt of claim 12, wherein the acid inthe acid addition salt is hydrochloric acid.
 15. The process accordingto claim 1 in which the improvement further comprises purifying saidisolated idelalisamine acid addition salt which comprises the steps of:(i) dissolving the salt in a solvent, and (ii) inducing crystallisationof the idelalisamine acid addition salt.
 16. The process according toclaim 15, wherein the acid in the addition salt of idelalisamine ishydrochloric acid.
 17. The process according to claim 16, wherein saidsolvent in step (i) is 2-Me-THF.